Method for systemic drug delivery through the nail

ABSTRACT

A method for systemically delivering a pharmaceutical composition to a human or animal, said method comprising forming an orifice in a nail of a human or animal by means of a laser-based device and applying a pharmaceutical composition in the orifice, wherein said method provides a controlled release of the pharmaceutical composition.

The present invention relates to a method for systemically delivering apharmaceutical composition to a human or animal, said method comprisingforming one or more orifices in a nail of the human or animal by meansof a laser-based device and applying a pharmaceutical composition in theorifice.

The nail plate is thick, hard, dense, and represents a barrier for drugsto be able to penetrate in a therapeutically required quantity. Althoughnail material is similar to the stratum corneum of the skin, beingderived from epidermis, it is composed primarily of hard keratin, whichis highly disulfide-linked, and is approximately 100-fold thicker thanstratum corneum. In order to deliver a sufficient amount of drug intoand across the nail plate, the permeability of the nail plate to thedrug must be enhanced.

U.S. Pat. No. 6,231,875 describes a method for topical treatment of nailand skin diseases. The patent relates to an acidified composition andmethods for increasing the permeability of a nail plate by means oftopically applying an acidified composition to the nail plate. U.S. Pat.No. 5,972,317 describes a method for treating diseased nails bytopically applying a nail-permeable composition to the nail plate whichcontains a proteolytic enzyme and a medicament. U.S. Pat. No. 5,181,914describes a medicating device for human diseased nails and adjacenttissue which contains a viscoelastic gel pad.

U.S. Pat. No. 5,947,956 describes a laser apparatus which is used tomake holes in of finger- and toe-nails to apply antifungals to theseholes for the treatment of onychomycosis U.S. Pat. No. 4,180,058describes a method for treating infections of the nail by drilling holesin the nail and placing a caustic-keratolytic agent in the opening toenlarge the opening, and adding a topical therapeutic agent.

The above-mentioned references describe methods or apparatuses fortreating nail diseases but none of the references suggests to use thenail, e.g. the healthy nail as drug delivery device to systemicallydeliver pharmaceutical compositions via nail orifices.

The present invention provides a method for systemically delivering apharmaceutical composition to the human or animal, said methodcomprising forming one or more orifices in the nail of the human oranimal by means of a laser-based device and applying a pharmaceuticalcomposition in the orifices, wherein said method provides a controlledrelease of the pharmaceutical composition.

“Orifice” as herein described means any small hole or depression thatpenetrates 80 to 100% of the nail plate, preferably 90 to 99%.

According to another aspect, the invention provides a method forsystemically delivering a pharmaceutical composition to the human oranimal, said method comprising forming one or more orifices in the nail,e.g. healthy nail of the human or animal by means of e.g. a laser-baseddevice, applying a pharmaceutical composition in the orifices, andoptionally adding a protective layer which prevents the pharmaceuticalcomposition from exiting the outer surface of the orifice and preventsbacteria and dirt from entering the orifice, to the outer surface of theorifices.

In one aspect the method of the invention provides a controlled delayedrelease, e.g. sustained release, e.g. prolonged release of thepharmaceutical composition that may be used for the continuous treatmentof diseases over a period of time.

In a further aspect the method of the invention provides a controlledfast release e.g. immediate release of the pharmaceutical composition.The fast release of pharmaceutical composition may be used to administerpharmaceutical compositions systemically and to avoid a first patheffect that may occur by oral administration. The delivery ofpharmaceutical composition through the orifice in the nail allows theadministration of the pharmaceutical agent directly on the well-perfusednail bed where it enters the blood-stream.

In addition, the method wherein one or more orifices are formed by meansof the laser-based device is accomplished with minimum patientdiscomfort due to the high precision and speed of the laser-baseddevice.

The orifices in the nail are formed preferably by means of thelaser-based device comprising a laser which is used to form at least oneorifice in the nail. Preferably, numerous orifices are formed in thenail. The orifice may traverse the entire nail or etch the naildepending on the desired mode of treatment and strength ofpharmaceutical composition. The diameter of the orifice is preferablyfrom 1 μm (micron) to 1 mm, more preferably from 50 μm (microns) to 200μm (microns), most preferably from 50 μm (microns) to 100 μm (microns).The orifices preferably are of cylindrical or conical shape.

Typically up to about 500 orifices may be formed in the nail, forexample about 50 to about 400, e.g. 100 to 300 orifices.

Any laser may be used provided it is capable of inducing ablation on thenail such as a photoablation laser. Photoablation refers to the meltingand explosion of hard tissues. Photoablation is achieved by pulsed laserirradiation of a selected wavelength, power and pulse duration accordingto the thermal, mechanical and spectral characteristics of the nail ofinterest. The deposited electromagnetic energy is almost entirelytransformed into mechanical energy (i.e.hν≈mv²/2) and the illuminatedregion is ejected in the form of debris escaping the orifice at ca.1'000m/s. In a preferred photoablation process, as the debris removes thedeposited energy, the irradiated nail is not heated thus minimizingdiscomfort.

The laser may be selected from an Erbium (Er):YAG laser, a Nd:YAG laser,a OPO laser, a Ho:YAG laser, a CO₂ laser, a UV laser, or an excimerlaser. A suitable UV laser is a nitrogen laser. Suitable excimer lasersinclude a Kr laser and a Xe laser. Most preferably, the laser is aEr:YAG (λ=2.94 μm) laser, a Ho:YAG laser (λ=2.1 μm), or a CO₂ gas laser(λ=10.6 μm). A combination of lasers may also be used. In a preferredembodiment of the invention, a second laser is used for micromachiningthe orifice. The ablation temperature is preferably greater than about100° C.

In one embodiment of the invention one or more small orifices are formedwith a single laser shot of ca. 50 μJ of power, ca. 250 μs of durationand the laser system operated at a repetition rate of 3 Hz.

In addition to the laser, the laser-based device may include one or moreof the following elements:

-   (a) a support to secure the nail e.g. by a clamp but leaving the    nail plate uncovered;-   (b) a computer controlled xyz translation stage module to position    the laser beam in the desired area of the nail. Preferably the    support (a) may be mounted on this translation stage so that the    laser beam is fixed and the toe or finger moves. Alternatively, the    toe or finger may be fixed and reflecting elements (e.g. mirrors)    are mounted on the translation stage to move the laser beam on the    selected parts of the nail plate;-   (c) a mirror e.g. dichroic mirror or prism may be used to coaxially    mix the laser beams from the laser(s);-   (d) an optical focussing element comprising at least one lens;-   (e) a computer to monitor the nail plate by means of a video camera    or charged coupled device camera which may be used to place the    laser beam(s) to the points of the nail plate where orifices are to    be formed by means of a computer controlled xyz translation stage    (b), and/or to control and/or select the different laser parameters    (e.g. the firing of the laser when the desired position of the xyz    translation stage (b) has been reached, or the laser power, the    pulse duration, or wavelength (e.g. if the laser is a tunable    laser);-   (f) a video camera or charged coupled device camera to monitor the    nail plate on the screen of a personal computer (e);-   (g) a feedback sensor (e.g. a photoacoustic sensor made of a    piezoelectric material) to ensure that the laser stops after the    orifice has reached a predetermined depth (e.g. the nail bed); and-   (h) an optical element to multiplex the laser beam(s) (e.g. a    diffractive optical element such as Dammann grating) to make more    than one orifice (e.g. an array of equally spaced orifices) by a    single shot thereby avoiding to make the orifices one-by-one in a    subsequent mode.

The pharmaceutical composition of the invention comprises at least oneactive ingredient. For the purpose of the invention, “active ingredient”means all substances that produce a pharmaceutical or therapeuticeffect. Active ingredients may include without limitationphotosensitizers, androgens, estrogens, nonsteroidal anti-inflammatoryagents, antihypertensive agents, analgesic agents, antidepressants,antibiotics, anticancer agents, anesthetics, antiemetics,antiinfectants, contraceptives, antidiabetic agents, steroids,anti-allergy agents, anti-migraine agents, agents for smoking cessation,and anti-obesity agents.

Examples of active ingredients include the following: acebutolol,acetylcysteine, acetaminophen, acetylsalicylic acid, acyclovir,alprazolam, alfacalcidol, allantoin, allopurinol, aloe vera, ambroxol,amikacin, amiloride, aminoacetic acid, amiodarone, amitriptyline,amlodipine, amoxicillin, ampicillin, ascorbic acid, astemizole,atenolol, beclomethasone, bee propolis, benserazide, benzalkoniumhydrochloride, benzocaine, betamethasone, bezafibrate, biotin,biperiden, bisoprolol, bromazepam, bromhexine, bromocriptine,budesonide, bufexamac, buflomedil, bupivacaine, buspirone, caffeine,camphor, captopril, carbamazepine, carbidopa, carboplatin, cefachlor,cefalexin, cefatroxil, cefazolin, cefixime, cefotaxime, ceftazidime,ceftriaxone, cefuroxime, selegiline, chloramphenicol, chlorhexidine,chlor-pheniramine, chlortalidone, choline, cyclosporin, cilastatin,cimetidine, ciprofloxacin, cisapride, cisplatin, clarithromycin,clavulanic acid, clomidine, clomipramine, clonazepam, clonidine,clotrimazole, codeine, cholestyramine, cromoglycic acid, cyanocobalamin,cyproterone, desogestrel, dexamethasone, dexpanthenol, dexamethasone,dextromethorphan, dextropropoxiphen, diazepam, diclofenac, digoxin,dihydrocodeine, dihydroergotamine, dihydroergotoxin, diltiazem,diphenhydramine, dipyridamole, dipyrone, disopyramide, domperidone,dopamine, doxycycline, enalapril, ephedrine, epinephrine,ergocalciferol, ergotamine, erythromycin, estradiol, ethinylestradiol,etoposide, Eucalyptus globulus, famotidine, felodipine, fenofibrate,fenoterol, fentanyl, flavin mononucleotide, fluconazole, flunarizine,fluorouracil, fluoxetine, flurbiprofen, folic acid, folinic acid,furosemide, gallopamil, gemfibrozil, gentamicin, Gingko biloba,glibenclamide, glipizide, clozapine, Glycyrrhiza glabra, griseofulvin,haloperidol, heparin, hyaluronic acid, hydrochlorothiazide, hydrocodone,hydrocortisone, hydromorphone, ipratropium hydroxide, ibuprofen,imipenem, indomethacin, insulin, iohexol, iopamidol, isosorbidedinitrate, isosorbide mononitrate, isotretinoin, ketotifen,ketoconazole, ketoprofen, ketorolac, labetalol, lactulose,levocarnitine, levodopa, levoglutamide, levonorgestrel, levothyroxine,lidocaine, lipase, imipramine, lisinopril, loperamide, lorazepam,lovastatin, medroxyprogesterone, menthol, methotrexate, methyldopa,methylprednisolone, methyltestosterone, metoclopramide, metoprolol,miconazole, midazolam, minocycline, minoxidil, misoprostol, morphine,multivitamin mixtures and combinations and mineral salts,N-methylephedrine, naftidrofuryl, naproxen, neomycin, nicardipine,nicergoline, nicotinamide, nicotine, nicotinic acid, nifedipine,nimodipine, nitrazepam, nitrendipine, nitroglycerine, nizatidine,norethisterone, norfloxacin, norgestrel, nortriptyline, nystatin,ofloxacin, omeprazole, ondansetron, pancreatin, panthenol, pantothenicacid, paracetamol, penicillin G, penicillin V, phenobarbital,pentoxifylline, phenoxymethylpenicillin, phenylephrine,phenylpropanolamine, phenyloin, piroxicam, polymyxin B, povidone-iodine,pravastatin, prazepam, prazosin, prednisolone, prednisone, prilocalne,progesterone, propafenone, propranolol, proxyphylline, pseudoephedrine,pyridoxine, quinidine, ramipril, ranitidine, reserpine, retinol,riboflavin, rifampicin, rutoside, salbutamol, salcatonin, salicylicacid, scopolamine, simvastatin, somatotropin, sotalol, spironolactone,sucralfate, sufentanil, sulbactam, sulfamethoxazole, sulfasalazine,sulpiride, sumatriptan, tamoxifen, tegafur, teprenone, terazosin,terbutaline, terfenadine, testosterone, tetracaine, tetracycline,theophylline, thiamine, ticlopidine, timolol, tranexamic acid,tretinoin, triamcinolone acetonide, triamterene, trimethoprim,troxerutin, uracil, valproic acid, vancomycin, verapamil, vitamin A,vitamin C, vitamin E, and zidovudine. A combination of activeingredients may also be used.

In another aspect the active ingredient of the pharmaceuticalcomposition of the invention may comprise a vaccine. Vaccines mayinclude without limitation Smallpox, Rabies, Plaque, Diphteria,Pertussis, Tuberculosis, Tetanus, Yellow Fever, Injectable PolioVaccine, Oral Polio Vaccine, Measales, Mumps, Rubella, Hepatitis B,Hepatitis C, Haemophilus influenza Typ B, Japanese Encephalitis,Biomanguinhos, Human Influenza Typ B (Hib), HIV, cancer.

The vaccines are preferably vaccines which require multiple inoculationto achieve protective titers such as Hepatitis B and Hepatitis C.

More preferably the vaccines are vaccines which require long contactwith dendritic cells to achieve a cytotoxic T-cell response such asHepatitis B, HIV, human Papilloma virus (HPV) and cancer. The nail bedhas a high concentration of Langerhans cells that stimulate the immuneresponse. Vaccines may be released to the nail bed by the method of theinvention. A robust immune response may be obtained by the slow releaseof vaccines by the method of the invention.

The cancer vaccines may be made of whole cancer cells or of substancescontained by the tumor. Preferably the cancer vaccines are selected fromthe group consisting of whole cancer cells, peptides, proteins,dendritic cells, gangliosides, heat-shock proteins, viral and bacterialvectors and nucleic acids.

The amount of active ingredient in the pharmaceutical composition mayvary from 0.1 weight percent, based on the total weight of thepharmaceutical composition, to 100 weight percent. Preferably the activeingredient is present in an amount of from 0.1 to 99, preferably from 20to 80, more preferably 30 to 70, weight percent, based on the totalweight of the pharmaceutical composition. The dose of active ingredientand exposure time depends on the number, diameter and shape of theorifices and on the nature and severeness of the disease to be treated.

Additional components may be used in the pharmaceutical compositions orapplied directly to an orifice prior to or following the addition of thepharmaceutical composition to the orifice. Such additional ingredientsinclude natural and/or artificial ingredients which are commonly used toprepare pharmaceutical compositions. Examples of additional ingredientsinclude surfactant (e.g. Aloe Vera), diluents, binders, disintegratingagents, anti caking agents, vitamins, botanicals, supplements, herbs,minerals, trace elements, amino acids (e.g., L. tryptophan), fibers,enzymes, fillers, buffers, colorants, dyes, antioxidants, preservatives,electrolytes, glidants, disintegrates, lubricants, and carriermaterials. A combination of additional ingredients may also be used.Such ingredients are known to those skilled in the art.

Following administration of the pharmaceutical composition to theorifice, a protective layer may be placed on the outer surface of theorifice. The protective layer prevents the pharmaceutical compositionfrom exiting the outer surface of the orifice and prevents bacteria anddirt from entering the orifice. Examples of materials useful to form aprotective layer include but are not limited to film forming polymers,nail varnish, porcelain, artificial nail, polymer foil, and a patch. Itis within the scope of the invention to color-coat the nail whether ornot a protective layer is applied.

The pharmaceutical composition may be in the form of a liquid,semi-solid, solid, solution, gel, emulsion, or powder.

The pharmaceutical compositions of the invention are useful fortreatment of the known indications of the particular active agentapplied. Useful applications include treatment of cancer or age-relatedmacular degeneration (AMD).

In one embodiment of the invention an image of the nail of either thefoot or hand is taken. A pattern and the geometry of a suitable array oforifices (e.g. 100 orifices) is calculated e.g. with a software tool.The designed array of orifices traversing the nail is patterned in thenail by laser photoablation. The orifices are filled with thepharmaceutical composition. A nail polish or patch may be used to sealthe nail.

In another embodiment of the invention, a laser patterns an array oforifices in a human nail. A surfactant is applied to the orifices e.g.non-ionic surfactant. The orifices are filled with a pharmaceuticalcomposition. A nail polish or patch may be used to seal the nail.

In another embodiment of the invention, a laser patterns an array oforifices in a human nail. The orifices are filled with aphotosensitizer. A nail polish or patch is used to seal the nail. Thephotosensitizer is activated with light. The type of light sourceincluding the wavelength and dose may vary depending on the condition tobe treated.

While the invention has been described with particular reference tocertain embodiments thereof, it will be understood that changes andmodifications may be made by those of ordinary skill within the scopeand spirit of the following claims.

1. A method for systemically delivering a pharmaceutical composition toa human or animal, said method comprising forming one or more orificesin a nail of the human or animal and applying the pharmaceuticalcomposition in the orifice.
 2. A method according to claim 1 wherein theorifices are formed by means of a laser.
 3. A method according to claim1 which provides a controlled release of the pharmaceutical composition.4. The method according to claim 3 wherein the laser is selected fromthe group consisting of a Erbium:YAG laser, a Nd:YAG laser, an OPOlaser, a Ho:YAG laser, a CO₂ laser, a UV laser, an excimer laser, andcombinations thereof.
 5. The method according to claim 1 wherein aprotective layer is placed on the outer surface of the orifice coveringthe nail.
 6. The method according to claim 1 wherein the pharmaceuticalcomposition comprises at least one active ingredient.
 7. The methodaccording to claim 6 wherein the active ingredient is a vaccine.
 8. Themethod according to claim 7 wherein the vaccine is selected from thegroup consisting of Smallpox, Rabies, Plaque, Diphteria, Pertussis,Tuberculosis, Tetanus, Yellow Fever, Injectable Polio Vaccine, OralPolio Vaccine, Measales, Mumps, Rubella, Hepatitis B, Hepatitis C,Haemophilus influenza Typ B, Japanese Encephalitis, Biomanguinhos, Hib,HIV and cancer.
 9. The method according to claim 7 wherein the vaccinerequires multiple inoculation to achieve protective titers.
 10. Themethod according to claim 7 wherein the vaccine requires long contactwith dendritic cells to achieve a cytotoxic T-cell response.
 11. Themethod according to claim 10 wherein the cancer vaccine comprises wholetumor cells or of substances contained by the tumor.
 12. The methodaccording to claim 10 wherein the cancer vaccine is selected from thegroup consisting of whole cancer cells, peptides, proteins, dendriticcells, gangliosids, heat-shock proteins, viral and bacterial vectors andnucleic acids.
 13. The method according to claim 6 wherein the activeingredient is selected from the group consisting of a photosensitizer,androgen, estrogen, nonsteroidal anti-inflammatory agent,antihypertensive agent, analgesic agent, antidepressant, antibiotic,anticancer agent, anesthetic, antiemetic, antiinfectant, contraceptive,antidiabetic agent, steroid, anti-allergy agent, anti-migraine agent,agent for smoking cessation, and anti-obesity agent.
 14. The methodaccording to claim 6 wherein the active ingredient is selected from thegroup consisting of acebutolol, acetylcysteine, acetaminophen,acetylsalicylic acid, acyclovir, alprazolam, alfacalcidol, allantoin,allopurinol, aloe vera, ambroxol, amikacin, amiloride, aminoacetic acid,amiodarone, amitriptyline, amlodipine, amoxicillin, ampicillin, ascorbicacid, astemizole, atenolol, beclomethasone, bee propolis, benserazide,benzalkonium hydrochloride, benzocaine, betamethasone, bezafibrate,biotin, biperiden, bisoprolol, bromazepam, bromhexine, bromocriptine,budesonide, bufexamac, buflomedil, bupivacaine, buspirone, caffeine,camphor, captopril, carbamazepine, carbidopa, carboplatin, cefachlor,cefalexin, cefatroxil, cefazolin, cefixime, cefotaxime, ceftazidime,ceftriaxone, cefuroxime, selegiline, chloramphenicol, chlorhexidine,chlor-pheniramine, chlortalidone, choline, cyclosporin, cilastatin,cimetidine, ciprofloxacin, cisapride, cisplatin, clarithromycin,clavulanic acid, clomidine, clomipramine, clonazepam, clonidine,clotrimazole, codeine, cholestyramine, cromoglycic acid, cyanocobalamin,cyproterone, desogestrel, dexamethasone, dexpanthenol, dexamethasone,dextromethorphan, dextropropoxiphen, diazepam, diclofenac, digoxin,dihydrocodeine, dihydroergotamine, dihydroergotoxin, diltiazem,diphenhydramine, dipyridamole, dipyrone, disopyramide, domperidone,dopamine, doxycycline, enalapril, ephedrine, epinephrine,ergocalciferol, ergotamine, erythromycin, estradiol, ethinylestradiol,etoposide, Eucalyptus globulus, famotidine, felodipine, fenofibrate,fenoterol, fentanyl, flavin mononucleotide, fluconazole, flunarizine,fluorouracil, fluoxetine, flurbiprofen, folic acid, folinic acid,furosemide, gallopamil, gemfibrozil, gentamicin, Gingko biloba,glibenclamide, glipizide, clozapine, Glycyrrhiza glabra, griseofulvin,haloperidol, heparin, hyaluronic acid, hydrochlorothiazide, hydrocodone,hydrocortisone, hydromorphone, ipratropium hydroxide, ibuprofen,imipenem, indomethacin, insulin, iohexol, iopamidol, isosorbidedinitrate, isosorbide mononitrate, isotretinoin, ketotifen,ketoconazole, ketoprofen, ketorolac, labetalol, lactulose,levocarnitine, levodopa, levoglutamide, levonorgestrel, levothyroxine,lidocaine, lipase, imipramine, lisinopril, loperamide, lorazepam,lovastatin, medroxyprogesterone, menthol, methotrexate, methyldopa,methylprednisolone, metoclopramide, metoprolol, miconazole, midazolam,minocycline, minoxidil, misoprostol, morphine, multivitamin mixtures andcombinations and mineral salts, N-methylephedrine, naftidrofuryl,naproxen, neomycin, nicardipine, nicergoline, nicotinamide, nicotine,nicotinic acid, nifedipine, nimodipine, nitrazepam, nitrendipine,nitroglycerine, nizatidine, norethisterone, norfloxacin, norgestrel,nortriptyline, nystatin, ofloxacin, omeprazole, ondansetron, pancreatin,panthenol, pantothenic acid, paracetamol, penicillin G, penicillin V,phenobarbital, pentoxifylline, phenoxymethylpenicillin, phenylephrine,phenylpropanolamine, phenyloin, piroxicam, polymyxin B, povidone-iodine,pravastatin, prazepam, prazosin, prednisolone, prednisone, prilocalne,progesterone, propafenone, propranolol, proxyphylline, pseudoephedrine,pyridoxine, quinidine, ramipril, ranitidine, reserpine, retinol,riboflavin, rifampicin, rutoside, salbutamol, salcatonin, salicylicacid, scopolamine, simvastatin, somatotropin, sotalol, spironolactone,sucralfate, sufentanil, sulbactam, sulfamethoxazole, sulfasalazine,sulpiride, sumatriptan, tamoxifen, tegafur, teprenone, terazosin,terbutaline, terfenadine, testosterone, tetracaine, tetracycline,theophylline, thiamine, ticlopidine, timolol, tranexamic acid,tretinoin, triamcinolone acetonide, triamterene, trimethoprim,troxerutin, uracil, valproic acid, vancomycin, verapamil, vitamin A,vitamin C, vitamin E, and zidovudine.
 15. The method according to claim1 wherein the pharmaceutical composition is in a form which is selectedfrom the group consisting of a liquid, semi-solid, solid, solution, gel,emulsion, and powder.
 16. The method according to claim 6 wherein theactive ingredient is present in the pharmaceutical composition in anamount of from 0.1 weight percent, based on the total weight of thepharmaceutical composition, to 100 weight percent.
 17. The methodaccording to claim 16 wherein the amount of active ingredient is from 20to 80 weight percent, based on the total weight of the pharmaceuticalcomposition.
 18. The method according to claim 17 wherein the amount ofactive ingredient is from 30 to 70 weight percent, based on the totalweight of the pharmaceutical composition.
 19. The method according toclaim 1 which is carried out using a laser-based device comprising alaser and at least one element selected from the group consisting of asupport, a computer controlled xyz translation stage module, a mirror,an optical focusing element comprising at least one lens, a computer, avideo camera, a charged coupled device camera, a feedback sensor, and anoptical element.
 20. The method according to claim 1 wherein thediameter of the orifice is from 1 μm (micron) to 1 mm.
 21. The methodaccording to claim 20 wherein the diameter of the orifice is from 50 μm(microns) to 200 μm (microns).
 22. The method according to claim 21wherein the diameter of the orifice is from 50 μm (microns) to 100 μm(microns).